The mammalian fatty acid amides and fatty acyl glycerol have been directly linked to the regulation of pain thresholds, body temperature, sleep cycles, appetite, and higher-level cognitive processes such as memory and learning. Nonetheless, how these lipids influence nervous system function is poorly understood. While some of these molecules trigger the central cannabinoid receptors CB1 and CB2, other members of this class lack described molecular targets. The enzyme fatty acid amide hydrolase (FAAH) controls the levels of fatty acid amides in vivo, setting the baseline function of their various corresponding physiologies. We have determined the three dimensional structure of this integral membrane protein in complex with novel inhibitors, and we are now prepared to expand these structure determination efforts to extend our knowledge of the mechanisms of action of this important enzyme. The studies described in this application (Project 2 of the Program Project) aim to determine higher resolution FAAH structures, as well as structures of human FAAH, apo-FAAH, and FAAH-inhibitor/product complexes. Furthermore, we will begin studies to solve the structure of the monoacylglycerol lipase which degrades neuronal 2-arachidonyl glycerol to complement our understanding of endocannabinoid metabolism. Information accrued from our studies will not only enlighten our understanding of these key enzymes but will also serve as a guide for the development of agents designed to intersect the endocannabinoid system in vivo, possibly to therapeutic benefit.